Chemotherapeutic approaches to cure infectious diseases and cancer depend on drugs that are selectively toxic to the disease-causing organism or the diseased cell. Viral infections and cancer pose the greatest challenge for chemotherapy because there is little biochemically to distinguish an infected or cancerous cell from a normal cell, and as a result many currently used drugs show little selectivity. There have been a number of approaches to increasing the selectivity of anticancer agents through the use of immunoconjugates, antibody-, gene-, and bacterial-directed enzymatic activation of prodrugs, and by capitalizing on elevated levels of certain enzymes and receptors within cancer cells. Other approaches have sought to exploit what is known about the molecular mechanisms of cancer to identify new biochemical targets for drugs. While all these methods can in principle lead to more selective chemotherapeutic agents, they are by no means easy to implement.
Recent advances in genomic sequencing and DNA chip technology now make it possible to determine the genetic makeup of diseases such as cancer. This, together with the ability to bind specific mRNA or DNA sequences with oligodeoxynucleotides (ODNs) or analogs such as peptide nucleic acids (PNAs) via simple base-pairing rules, or DNA with polyamides via its own set of rules, has opened the door for new approaches to chemotherapy that make direct use of genetic information. Current approaches in this category can be classified as anti-sense or anti-gene, and are based on specifically binding to, and either interfering with, or damaging, the targeted nucleic acid sequence. What makes these approaches so attractive is the ease by which it would seem possible to tailor chemotherapeutic agents for individual patients based on genetic information that could be obtained about their disease states from DNA chips. As promising as both approaches are, it is difficult to predict the therapeutic effect of targeting a viral or cancer-specific nucleic acid sequence, and in many such applications of antisense technology, the therapeutic effect has been found not to involve an antisense mechanism.
The goal of chemotherapy is to design or discover drugs that are selectively toxic to the diseased cell or the disease-causing organism. This is a quite difficult challenge for cancer chemotherapy, however, because there is often little biochemically to distinguish a normal cell from a cancerous cell. Most chemotherapeutic drugs found by traditional screening approaches have been found to interfere with replication and owe their selectivity to the fact that cancer cells divide more rapidly than normal cells. Unfortunately, the chemotherapeutic indices for these drugs are often quite low. More recently, new approaches to chemotherapy have sought to take advantage of what has been learned about the biochemistry of cancer cells to design more effective drugs. Promising as these approaches are, individual drugs would have to be developed for each type of cancer, and would still be susceptible to drug resistance through mutations in the target enzymes or proteins that are acquired by the rapidly dividing cancer cells.
Another approach to obtaining highly selectively chemotherapeutic agents is to further increase the selectivity of known agents by selectively targeting prodrugs, or prodrug metabolizing enzymes to diseased cells. Most notable among such approaches is ADEPT (antibody directed enzyme prodrug therapy), in which an antibody that recognizes a disease-specific antigen is linked to a prodrug metabolizing enzyme which leads to the release of a cytotoxic agent outside the cell. A related approach involves targeting of a gene coding for the prodrug metabolizing enzyme (GDEPT) by either chemical or viral methods to activate the prodrug within the cell. Unfortunately, the success of these types of approaches also depends on the existence of significant biochemical differences between normal and diseased cells, and would likewise be susceptible to drug resistance.
An ideal type of prodrug chemotherapy would involve activation of the prodrug specifically within the diseased cell without the need for targeting, and without the need to know the biochemical basis of the disease.